Colorectal carcinoma from Saudi Arabia Analysis of MLH-1, MSH-2 and p53 genes by immunohistochemistry and tissue microarray analysis

To document the incidence and role of p53 and DNA mismatch repair proteins in colorectal carcinomas, and to evaluate the relative frequency of major molecular pathways in colorectal cancers from Saudi Arabia. We collected the formalin fixed, paraffin embedded tissues from 154 colorectal tumors [83 patients from King Faisal Specialist Hospital and Research Centre and 71 from Saudi Aramco Dhahran Health Centre] between January 1989 and December 2003. We analyzed the p53 and mismatch repair gene expression [hMSH-2, hMLH-1] by immunohistochemistry in tissue microarray format. Expression loss of at least one mismatch repair gene was found in 33.8% of cases and significantly associated with the right-sided tumor location [p=0.0047]. The p53 positivity was observed in 57.5% of tumors, and was inversely linked to expression loss of mismatch repair genes [P=0.0102]. The strong confirmation of the previously established associations between tumor phenotype, and mismatch repair gene alteration provided strong evidence for the validity of our experimental approach. Together with the higher incidence of right sided location in Saudi [46.6%] than in Western colon cancers [34.9%], the observed high prevalence of mismatch gene expression loss in Saudi tumors argues for a higher importance of microsatellite instability in this population. If confirmed, it will be interesting to see whether an increased level of familial or sporadic microsatellite instability cases is causing this variation

Tissue microarrays for high-throughput molecular pathology

Modern research technologies, including DNA, protein, and antibody microarrays identify a steadily growing number of clues that are useful in molecular disease classification, drug development, and the prediction of response to treatment. Subsequent validation of the clinical importance of such candidate genes or proteins requires large-scale analysis of human tissues. To date, this analysis constitutes an important bottleneck in the process of discovery because tissue analysis by the conventional slide-by-slide strategy is slow and expensive. To overcome these limitations, tissue microarray [TMA] technology has been developed. TMA allows for the simultaneous analysis of up to 1,000 tissue samples in a single experiment, using all types of in-situ analyses including immunohistochemistry [IHC], fluorescence in situ hybridization [FISH], and RNA in situ hybridization [RNA-ISH]. TMA technology has the potential to greatly facilitate the translation of basic research into clinical practice. Potential applications include the establishment of associations between molecular changes and clinical endpoints, testing of potential therapeutic targets using tissue samples from specific cancer patients, standardization of molecular detection of targets, and rapid translation of results from cell lines and animal models to human cancer. Because of its beneficial economic aspects and ability to differentiate ethnic differences in tumor biology, TMA applications may become particularly important in developing countries